Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice

The present study investigated the chronic efficacy of oleanolic acid (OA), a triterpenoid selected from our recent screening, on hyperglycemia in type-2 diabetic mice. C57BL/6J mice were fed a high-fat diet followed by low doses of streptozotocin to generate a type-2 diabetic model. OA (100 mg/kg/d...

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Main Authors:	Zeng, Xiao-Yi, Wang, Yi-Ping, Cantley, James, Iseli, Tristan J., Molero, Juan Carlos, Hegarty, Bronwyn D., Kraegen, Edward W., Ye, Yang, Ye, Ji-Ming
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408432/

id	pubmed-3408432
recordtype	oai_dc
spelling	pubmed-34084322012-08-02 Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice Zeng, Xiao-Yi Wang, Yi-Ping Cantley, James Iseli, Tristan J. Molero, Juan Carlos Hegarty, Bronwyn D. Kraegen, Edward W. Ye, Yang Ye, Ji-Ming Research Article The present study investigated the chronic efficacy of oleanolic acid (OA), a triterpenoid selected from our recent screening, on hyperglycemia in type-2 diabetic mice. C57BL/6J mice were fed a high-fat diet followed by low doses of streptozotocin to generate a type-2 diabetic model. OA (100 mg/kg/day) was administered orally for 2 weeks with its effects monitored for 6 weeks. High-fat feeding and streptozotocin generated a steady hyperglycemia (21.2±1.1 mM) but OA administration reversed the hyperglycemia by ∼60%. Interestingly, after the cessation of OA administration, the reversed hyperglycemia was sustained for the entire post-treatment period of the study (4 weeks) despite the reoccurrence of dyslipidemia. Examination of insulin secretion and pancreas morphology did not indicate improved β-cell function as a likely mechanism. Urine glucose loss was decreased with substantial improvement of diabetic nephropathy after the OA treatment. Pair-feeding the OA-treated mice to an untreated group ruled out food intake as a main factor attributable for this sustained reduction in hyperglycemia. Studies with the use of glucose tracers revealed no increase in glucose influx into muscle, adipose tissue or liver in the OA-treated mice. Finally, we analyzed key regulators of gluconeogenesis in the liver and found significant increases in the phosphorylation of both Akt and FoxO1 after treatment with OA. Importantly, these increases were significantly correlated with a down-regulation of glucose-6-phosphatase expression. Our findings suggest triterpenoids are a potential source of new efficacious drugs for sustained control of hyperglycemia. The liver appears to be a major site of action, possibly by the suppression of hepatic glucose production via the Akt/FoxO1 axis. Public Library of Science 2012-07-30 /pmc/articles/PMC3408432/ /pubmed/22860063 http://dx.doi.org/10.1371/journal.pone.0042115 Text en © 2012 Zeng et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Zeng, Xiao-Yi Wang, Yi-Ping Cantley, James Iseli, Tristan J. Molero, Juan Carlos Hegarty, Bronwyn D. Kraegen, Edward W. Ye, Yang Ye, Ji-Ming
spellingShingle	Zeng, Xiao-Yi Wang, Yi-Ping Cantley, James Iseli, Tristan J. Molero, Juan Carlos Hegarty, Bronwyn D. Kraegen, Edward W. Ye, Yang Ye, Ji-Ming Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice
author_facet	Zeng, Xiao-Yi Wang, Yi-Ping Cantley, James Iseli, Tristan J. Molero, Juan Carlos Hegarty, Bronwyn D. Kraegen, Edward W. Ye, Yang Ye, Ji-Ming
author_sort	Zeng, Xiao-Yi
title	Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice
title_short	Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice
title_full	Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice
title_fullStr	Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice
title_full_unstemmed	Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice
title_sort	oleanolic acid reduces hyperglycemia beyond treatment period with akt/foxo1-induced suppression of hepatic gluconeogenesis in type-2 diabetic mice
description	The present study investigated the chronic efficacy of oleanolic acid (OA), a triterpenoid selected from our recent screening, on hyperglycemia in type-2 diabetic mice. C57BL/6J mice were fed a high-fat diet followed by low doses of streptozotocin to generate a type-2 diabetic model. OA (100 mg/kg/day) was administered orally for 2 weeks with its effects monitored for 6 weeks. High-fat feeding and streptozotocin generated a steady hyperglycemia (21.2±1.1 mM) but OA administration reversed the hyperglycemia by ∼60%. Interestingly, after the cessation of OA administration, the reversed hyperglycemia was sustained for the entire post-treatment period of the study (4 weeks) despite the reoccurrence of dyslipidemia. Examination of insulin secretion and pancreas morphology did not indicate improved β-cell function as a likely mechanism. Urine glucose loss was decreased with substantial improvement of diabetic nephropathy after the OA treatment. Pair-feeding the OA-treated mice to an untreated group ruled out food intake as a main factor attributable for this sustained reduction in hyperglycemia. Studies with the use of glucose tracers revealed no increase in glucose influx into muscle, adipose tissue or liver in the OA-treated mice. Finally, we analyzed key regulators of gluconeogenesis in the liver and found significant increases in the phosphorylation of both Akt and FoxO1 after treatment with OA. Importantly, these increases were significantly correlated with a down-regulation of glucose-6-phosphatase expression. Our findings suggest triterpenoids are a potential source of new efficacious drugs for sustained control of hyperglycemia. The liver appears to be a major site of action, possibly by the suppression of hepatic glucose production via the Akt/FoxO1 axis.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408432/
_version_	1611546532827365376

Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice

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